Within lung adenocarcinoma, histology is heterogeneous and associated with tissue invasion and clinical outcomes. The spectrum of intra-tumoral histological heterogeneity in adenocarcinoma suggests nvasiveness represents a continuum of disease from noninvasive bronchioloalveolar carcinoma (BAG) to adenocarcinoma mixed subtype with BAG component to pure invasive adenocarcinoma. The molecular events essential to this transition in the lung are presently unknown. In this study, we focus on invasion, a significant biological and morphological characteristic of cancer with direct clinical implications in terms of metastasis and outcome. In preliminary gene expression profiling experiments, we identified the type II TGF- /? receptor (TGF/SRII), which was expressed at significantly lower levels in invasive tumors, as one of the most interesting genes in the acquisition of lung invasiveness classifiers. We hypothesize that repression of TGFBRII in lung adenocarcinoma is required to mediate tumor/stromal interactions that precede the acquisition of invasiveness in lung adenocarcinoma. In this grant proposal, we will address the main hypothesis in the following Specific aims: 1. Determine the direct role of Tgfbr2 repression on adenocarcinoma invasiveness in vivo using genetic model of murine lung adenocarcinoma. We will create a novel animal model of invasive lung adenocarcinoma in mice with pulmonary targeted deletion of Tgfbr2 and mutation of K-Ras. In Aim 2, we will determine the requirement for CCL5 (Rantes) in mediating tumor- stromal interactions that are important for invasion of TGFBRII knock-down cells. CCL5 was identified as a potential downstream mediator of TGFB signaling in invasive tumors. In Aim 3, we will create a large adenocarcinoma tumor microarray to examine the clinical significance of TGFBRII immunostaining human lung adenocarcinoma. In these studies, we will demonstrate the importance of TGFBR2 pathways in modulating tumor epithelial/stromal interactions important for the acquisition of invasiveness in lung adenocarcinoma and we expect to identify the mechanisms of this activity. The results of these studies will facilitate the attainment of the long-term goals, which are to develop clinically available assays to predict invasive propensity in adenocarcinoma tissue specimens and to develop and test pharmacologic agents that will reduce invasiveness in patients with lung cancer or prevent the development of invasive tumors in individuals at high risk for lung cancer.